Xanthone carboxylic acids and derivatives

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions are also disclosed. 7Acetylxanthone-2-carboxylic acid is illustrated as representative of the class.

United States Patent Pfister et al. Oct. 7, 1975 [5 XANTHONE CARBOXYLIC ACIDS AND [58] Field of Search 260/335 DERIVATIVES [75] Inventors: Jurg R. Pfister, Los Altos; [an T. [56} References Cited Harrison; John H. Fried, both of UNITED STATES PATENTS Palo Alto, all Of Calif. 3,642,997 2/l972 ShCfl et a]. 424/250 3,7 6,76 12 7 B u 2 ()3 [73] Assignee: Syntex (U.S.A.) Inc., Palo Alto. 0 8 H9 2 6 l 35 Calif Primary ExaminerNorma S. Milestone [22] Filed: Feb. 7, 1974 Attorney, Agenr, or FirmGerard A. Blaufarb; Walter D W W'l PP NOZ 440.326 H reger, illiam B d ker Related US. Application Dala [57] ABSTRACT [60] Division of Ser. No. 259,853, June 5, I972, Pat. No. Compositions containing and methods employing, as 33181142 which is continuatiofl-in-pafl the essential ingredient, xanthone carboxylic acid 8 i972 3-8737l4i wh'ch compounds which are useful in the treatment of allera continuation-impart of Ser. No. 162,696, July 14, g Conditions Methods for preparing these 1971, abandoned,

pounds and compositions are also disclosed. 52 0.5. CI. 260/335; 424/278; 260/293.58; 3 filflfxig g iffif z 260/268; 260/21 1 p [51 lnt. Cl. C07D 311/86 18 Claims. N0 Drawings 1 XANTHONE CARBOXYLIC ACIDS AND DERIVATIVES This is a division of application Ser. No. 259,853 filed June 5, 1972, now US. Pat. No. 3,818,042, which is a continuation-in-part of application Ser. No. 217,383 filed Jan. 12, I972, now US. Pat. No. 3,873,? l4, which in turn is a continuation-in-part of application Ser. No. 162,696filed July l4, I971 now abandoned. The present invention is directed to xanthone carboxylic acid compounds and to compositions containing and methods utilizing these compounds as the essential ingredient in the treatment of symptons associated with allergic manifestations, for example, asthmatic conditions.

In a first aspect, the present invention relates to novel xanthone carboxylic acid compounds selected from those represented by the following formulas:

Icon ammo" o o an the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein each R is a group selected from these of the fomulas:

in which R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl, 4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12 carbon atoms, and R is hydrogen, lower alkyl or cycloalkyl, R is hydrogen; lower alkyl; cycloalkyl; phenyl; substituted phenyl in which the substituent is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, or cyano', or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and sulfur.

Thus included within the scope of the present invention are the C-5 and C-7 secondary and tertiary lhydroxyalkyl substituted xanthene-Z-carboxylic acid compounds and the hydroxy esters (preferably acetoxy) and hydroxy ethers (preferably methoxy) thereof and the C-5 and C-7 acyl substituted xanthone-Z-carboxylic acid compounds.

In a second aspect, the present invention is directed to a method useful for relieving symptoms associated with allergic manifestations such as are brought about by antigen-antibody (allergic) reactions. In the relief of these symptoms, the method hereof serves to inhibit the effects of the allergic reaction when administered in an effective amount. While not intending to be bound by any theoretical mechanism of action, the method hereof is believed to operate by inhibiting the release and/or the action of toxic products, e.g. histamine, 5-

2 hydroxytryptamine, slow releasing substance (SRS-A), and others, which are produced as a result of a combination of specific antibody and antigen (allergic) reaction. These properties make the subject compounds particularly useful in the treatment of various allergic conditions.

This aspect of the present invention thus relates to a method useful for inhibiting the effects of the allergic reaction which comprises administering an effective amount of a compound selected from those represented by the following formulas:

and the pharmaceutically acceptable non-toxic esters, amides, and salts thereof: wherein each R is a group selected from those of the formulas:

in which R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyramZ-yl, tetrahydropyran-4-yl, 4-alkoxytetrahydropyrani-yl, or carboxylic acyl containing up to 12 carbon atoms, and R is hydrogen, lower alkyl or cycloalkyl, and R is hydrogen; lower alkyl; cycloalkyl; phenyl, substituted phenyl in which the substituent is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and sulfur, or a pharmaceutically acceptable non-toxic composition incorporating said compounds, esters, amides or salts as an essential ingredient.

The compounds of the present invention are also smooth muscle relaxants, e.g. bronchial dilators, and are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance, in the treatment of broncho constriction. The compounds of the present invention are also vasodilators and are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance, in renal and cardiac disorders.

The present invention, in a third aspect, is directed to pharmaceutical compositions useful for inhibiting the effects of the allergic reaction comprising an effective amount of a compound selected from those represented by the following formulas:

coon R coon l and the pharmaceutically acceptable esters, amides, and salts thereof; wherein each R is a group selected from those of the formulas:

in which R is hydrogen, lower alkyl, cycloalkyl, tetrahydrofuran-Z-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl, 4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to l2 carbon atoms, and R is hydrogen, lower alkyl or cycloalkyl, and R is hydrogen; lower alkyl; cycloalkyl; phenyl; substituted phenyl in which the substituent is halo, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, or cyanol or a monocyclic aromatic heterocyclic group having five or six total memberts, one or two of which are selected from nitrogen, oxygen, and sulfur, in admixture with a pharmaceutically acceptable nontoxic carrier.

in the practice of the method of the present invention, an effective amount of a compound of the present invention or pharmaceutical compositions thereof, as defined above, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents, such as antibiotics, hormonal agents, and so forth. These compounds or compositions can thus be administered orally, topically, parenterally, or by inhalation and in the form of either solid, liquid, or gaseous dosages including tablets, suspensions, and aerosols, as discussed in more detail hereinafter. The administration can be conducted in single unit dosage form with continuous therapy or in single dose therapy ad libitum. In the preferred embodiments, the method of the present invention is practiced when relief of symptoms is specifically required, or perhaps, imminent; however, the method hereof is also usefully practiced as continuous or prophylactic treatment.

In view of the foregoing as well as in consideration of the degree of severity of the condition being treated, age of subject, and so forth, all of which factors being determinable by routine experimentation by one skilled in the art, the effective dosage in accordance herewith can vary over a wide range. Generally, an effective amount ranges from about 0.005 to about I mg. per kg, of body weight per day and preferably from about 0.01 to about I00 mg. per kg. of body weight per day. ln alternate terms, an effective amount in accordance herewith generally ranges from about 0.5 to about 7,000 mg. per day per subject.

Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids, or

gases. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carriers can be selected from the various oils including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium carbonate, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Suitable pharmaceutical carriers and their formulation are described in "Remingtons Pharmaceutical Sciences" by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the host.

The compounds of the present invention demonstrate activity as inhibitors of the effects of the allergic reaction as measured by tests indicative of such activity involving passive cutaneous anaphylaxis as substantially described, for example, by .l. Goose et al., Immunology, 16, 749 (I969).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Sequence A O COG! 4 4 l Q- R coon wherein R is lower alkyl, preferably methyl;

R is acyl; and

halo is bromo, chloro, fluoro, or iodo, preferably bromo.

With reference to the above sequence, an ortho or para substituted (R phenol 1) is condensed with the l,3-dicarbo-(lower)alkoxy-4-halobenzene compound (2) in the presence of cuprous oxide optionally in organic liquid reaction medium, preferably an organic amide such as dimethyl acetamide, dimethyl formamdie, N-methyl pyrrolidone, tetramethylurea, and so forth, to prepare the corresponding l,3-dicarbo(lower- )alkoxy-4- (oor p-substituted phenyloxy)-benzene compound (3).

The reaction is preferably conducted in an inert organic reaction medium, such as those listed above, or suitable mixtures of one or more of such medium. The rection is further conducted at temperatures ranging from about to about 220C, preferably about from l20 to 200C, and for a period of time sufficient to complete the reaction, ranging from about two hours to about 24 hours.

The reaction consumes the reactants on the basis of one mole of the substituted phenol per mole of the dicarbo(lower)-carboxyhalobenzene per half mole of cuprous oxide. However, the amounts of the reactants to be employed are not critical, some of the desired compound (3) product being obtained when employing any proportions thereof. In the preferred embodiments, the reaction is conducted by reacting from about one to about three moles of the substituted phenol compound with about from one to about 1.2 moles of the dicarbo(lower)carboxyhalobenzene compound in the presence of from about 0.5 to about 0.6 moles of the euprous oxide. The inert organic reaction medium, if employed, is used in solvent amounts.

Thereafter. the prepared compound (3) is based hydrolyzed to give the corresponding 1,3-dicarboxy-4-(oor p-substituted phenyloxy)-benzene (4). The base hydrolysis conditions can be any employed conventionally in the art. Generally, the hydrolysis reaction is conducted using an alkali metal hydroxide at about 50 to about 90C and for a period of time sufficient to complete the reaction, ranging from about minutes to about 60 minutes, preferably in the presence of inert organic reaction media such as those normally employed in organic chemical reactions of this type, e.g. aqueous alkanol solutions. Although two moles of base are required per mole of compound (3), the amounts employed are not critical to produce the desired hydrolysis. Preferably from about three to about five moles of base are employed per mole of compound (3) and the reaction media, if employed, is used in solvent amounts.

The thus prepared diacid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or preferably, polyphosphoric acid (PPA), to give the corresponding 5- or 7- substituted xanthone-Z-carboxylic acid compound (5 The reaction is preferably, but optionally, conducted in an inert organic reaction medium including those usually employed in organic chemical reactions, such as dimethysulfoxide, sulfolane, benzene, toluene, and so forth. The reaction is further conducted at temperatures ranging from about to about 180C, and for a period of time sufficient to complete the reaction ranging from about 15 minutes to about minutes,

Although the reaction consumes the reactants on the basis of one mole of compound (4) per mole of cyclizing reagent, the reaction can be performed using any proportions of reactants. In the preferred embodiments, however, the reaction is conducted using from about 20 to about 50 moles of the cyclizing reagent per mole of starting compound (4).

The compounds of the present invention in the 5- or 7-(secondary hydroxyalkyl )-xanthone-2-carboxylic acid series are prepared from the corresponding 5 or 7-acyl compounds, prepared as described above. The 5 or 7-acylxanthone-2- carboxylic acids are converted to the corresponding acid ester such as with alkyl iodide under basic conditions. The acyl ester is then reduced such as with sodium borohydride to give the 5- or 7(secondary hydroxyalkyl)-xanthone-2-carboxylic acid ester which can be hydrolyzed to the acid.

The 5- or 7-(tertiary hydroxyalkyl)-xanthone-2-carboxylic acids hereof are prepared by treating the 5- or 7-acylxanthone carboxylic acid esters with a lower alkyl or cycloalkyl Grignard reagent followed by hydrolysis of the ester.

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

SequenceB COOH l COOH coon coon Sequence B Continued I 3 I R COOR R 2 H OH R 2 1' P COOH wherein R" is R exclusive of hydrogen, R is R exclusive of hydrogen, and R is lower alkyl, preferably methyl.

With reference to the above reaction sequence, xanthone-Z-carboxylic acid (6) prepared as described above, is reduced such as with potassium hydroxide in hydrazine, zinc and potassium hydroxide in ethanol, lithium aluminum hydride, and like reduction methods to prepare the corresponding xanthene-Z-carboxylic acid (7). This compound is conventionally esterified (R by means known to those skilled in the art, for example, by treatment of the acid with diazoalkane or with alkanol and sulfuric acid. The resultant ester (8) is then acylated under Friedel-Crafts conditions with an acid chloride in the presence of aluminum chloride to give the corresponding 7-acyl compound (9).

The result compound (9) is oxidized, such as under known Jones conditions, to give the corresponding 7- acylxanthone-2-carboxylate esters (l0), which can be hydrolyzed, as described above, to give the 7-acylxanthone-2-carboxylic acid compounds Compounds 10) can also be reduced, such as by the known method using sodium borohydride, to give the corresponding 7-( secondary hydroxyalkyl)-xanthone- COOH COOH

Z-carboxylate esters (l l) which can be hydrolyzed to the acid products (13).

Compounds 10) can also be treated with alkyl or cycloalkyl (i.e. R") Grignard reagent, under known Grignard reaction conditions. to give the corresponding 7(tertiary hydroxyalkyl)-xanthone-2-carboxylate esters (12) which can be hydrolyzed to the acid products (14).

Alternatively, the compounds of formula (9) can be reduced or treated with Grignard reagent, as described above, to prepare the corresponding 7-(secondary and tertiary hydroxyalkyl) xanthene compounds. These can be acylated via conventional secondary and tertiary acylation techniques to give the corresponding esters which are oxidized under Jones conditions to prepare the corresponding 7-(secondary and tertiary acyloxyalkyl)-xanthone-carboxylic acid esters which, when hydrolyzed under base conditions, gives the corresponding 7-(secondary and tertiary hydroxyalkyl)-xanthone- Z-carboxylic acid products (13 and I4).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

Sequence C COOR o 3 c I c 2 C00! I 0 o 0 CH c002 cicH' ("m2 COOR 3 0 c|-| coon ouc cooks CH 0 OHC COOH With reference to the above reaction sequence, xangive the oxido derivative (19). This compound is thene-Z-carboxylic acid ester (8) is reacted with chlotreated with periodic acid or with perchloric acid and roacetyl chloride under Friedel-Crafts conditions to sodium periodate to give the 7-formylxanthone-2-cargive compound (16). This compound is then oxidized boxylate ester (20) which is hydrolyzed to the acid as described above to give the corresponding xanthone 45 product (21).

(17) which is reduced as described above to give the An alternative method for the preparation of certain hydroxy compound (l8). The resultant compound is of the C-5 substituted compounds hereof is illustrated treated with sodium hydride in dimethylformamide to y the following qu nce:

Sequence D CH coon 2'/ 2 halo Sequence DContinued (OCH CH2 2 R COOH 1 a COOH C O CH OH 2/ R2'/ R (26) (27) COOH C OH 2 l R wherein each of R", R R and halo is as above decompound fined. V

With reference to the above reaction sequence th (m I 5-substituted-xanthone-2-carboxylic compounds are prepared following the above reaction Sequence A (1+2 4 5) l the P stamng which can be converted to the corresponding alcohol P0unds (22) The resultant compound? (25 of upon treatment with aqueous base, to give the product esters are oxidized with chromium trioxide in acetic acids (27 acid-acetic flnhydrlde to give the y coompolmds The compound S-methylxanthone-Z-carboxylic acid, (26) which are reduced or treated with Grignard rea- 5 prepared a described if, Sequence A (1 5) from as above f q 8'? the respecuve methylphenol, can be oxidized under known Thiele n y and tertiary y y y l- Q conditions to give the corresponding 5-formylxanboxyhc acid Products and Alternative to the thone-2-carboxylic acid. This method is also useful for above procedure. the 5-substituted xanthone-Z-can re aring 7-formylxanth0ne-2-carb0xylic acid. boxylic i (25) can converted P" g A particularly preferred method for the preparation ester and treated wlth N'bl'omosucclmmlde W of certain of the compounds hereof is represented as pare the corresponding S-(substituted bromomethyl) f ll -J Sequence E I CH3\- CH3 4 hill 0 O coon R4 R4 o (inwherein R is as defined above.

With reference to the above sequence, an appropriate phenol (29) is treated with lm3-dimethyl-4-halo- (preferably iodo) benzene (30), as described above, to prepare the corresponding l,3-dimethyl-4-phenyloxy benzene (3] This compound is then oxidized such as with potassium permanganate in aqueous t-butanol, to give the corresponding l,3-dicarboxy-4-phenyloxybenzene (32). This compound is then cyclizcd, as described above, to give the corresponding xanthone-2- carboxylic acid (33) which can be modified as described above to prepare the product C-S or C-7 substituted compounds hereof.

The carboxylic acyl esters of the secondary and tertiary hydroxy alkyl substituted compounds (i.e. R'=)\ carboxylic acyl) are prepared as described above or by secondary and tertiary alcohol esterification methods known per se. One such method involves treating the products represented by Formulas l 3) and (27) with a carboxylic acid chloride or carboxylic acid anhydride in the presence of a base, preferably pyridine, at temperatures ranging from about 60 to about 90C and for a period of time ranging from about I to about 2 hours to give the corresponding secondary carboxylic acyloxy alkyl substituted xanthone-Z-carboxylic acid compound. Likewise, by treating the products of Formulas (l4) and (28) with a carboxylic acid chloride and dimethylaniline in tetrahydrofuran or with a mixed carboxylic acid, p-toluenesulfonic acid anhydride, the corresponding tertiary carboxylic acyloxy alkyl substituted xanthone-Z-carboxylic acid compounds are prepared. See Harrison and Harrison, Compendium of Organic Synthetic Methods, Wiley-lnterscience, New York (l97l) 28l and 2 and the references cited thereon.

The alkyl and cycloalkyl ethers of the secondary hydroxyalkyl series (R'=alkyl, cycloalkyl) are prepared by treatment of the xanthone acid ester with the appropriate alkyl or cycloalkyl halide and sodium hydride in, e.g. dimethylformamide, followed by hydrolysis, as described above. The etherification reaction is conducted at from about 50 to about 80C and for from about 1 to about 5 hours. In the tertiary alcohol series, the alkyl and cycloalkyl ethers are prepared by treating the precursor acyl compound, eg 7-acetylxanthone-2-carboxylic acid ester, under Grignard conditions, as described above, but in the presence of appropriate alkyl or cycloalkyl iodide or bromide and hexamethylphos phoramide to concomitantly afford the alkyl or cycloalkyl ether of the tertiary alcohol, followed by hydrolysis as described above. See Harrison and Harrison, Compendium of Organic Synthetic Methods, Wiley-interscience, New York (197i 323 and the references cited thereon.

coon

COOH

The t-butoxy ethers are prepared by treating the alcohol with isobutene in the presence of boron trifluoride and phosphoric acid in, e.g. methylene chloride, at temperatures of from about 10 to about 30C and for from 10 to about 24 hours, or more, followed by hydrolysis of the acid ester group, as described above.

The tetrahydrofuran-2-yloxy and tetrahydropyran-2 yloxy ethers in the secondary and tertiary alcohol series are prepared by treatment with dihydrofuran or dihydropyran in the presence of p-toluenesulfonic acid and organic reaction medium, e.g. benzene, at about room temperature up to reflux, for from about 2 to about 5 days, followed by hydrolysis of the acid ester, as described above.

The 4-alkoxytetrahydropyran-4-yloxy ethers in the secondary and tertiary alcohol series are prepared by treatment of the alcohol with 4-alkoxy-5 ,6-dihydro-2H- pyran, as described above for the preparation of the furanyl and pyranyl ethers, followed by acid ester hydrolysis. Treatment of the 4-alkoxytetrahydropyran-4- yloxy ether with aluminum chloride and lithium aluminum hydride in organic reaction medium affords the corresponding cetrahydropyran-4-yloxy ethers which are oxidized to give the corresponding ethers in the xanthone acid series. The latter can be directly prepared by treating the alcohol with 4-bromotetrahydropyran and base. See Harrison and Harrison, Compendium of Organic Synthetic Methods, Wiley-lnterscience, New York (1971) l29 and the references cited thereon.

The acid esters of the xanthone-Z-carboxylic acids hereof are prepared as described above (e.g. 7 8) upon treatment of the acid with ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of a trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a suitably protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, and hydrolyzing the protecting group of the ester thus formed with dilute acid. In the sulfo series, the carboxylic acid esters are preferably prepared with the desired lower alkanol in the absence of acid catalyst.

The amides of the xanthone-Z-carboxylic acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkylamine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine.

The salts of the xanthone-2-carboxylic acids hereof are prepared by treating the corresponding acids with pharmaceutically acceptable base. Representative salts derived from such pharmaceutically acceptable bases are sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, ferric, zinc, manganous, aluminum, manganic, the salts of trimethylamine, triethylamine, tripropylamine, B-(dimethylamino)ethanol, triethanolamine, B-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, chlorine, betaine, ethylenediamine, glucosamine, methyl glucamine, theobromine, purines, piperazine, piperidine, polyamine resins, caffeine, procaine or the like. The reaction is conducted in an aqueous solution, alone or in combination with an inert, water miscible organic solvent, at a temperature of from about C to about 100C, preferably at room temperature. Typical inert, water miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal salts are prepared, such as the calcium salts or magnesium salts of the acids the free acid starting material is treated with about one half molar equivalent of pharmaceutically acceptable base. When the aluminum salts of the acids are prepared about one third molar equivalent of the pharmaceutically acceptable base are employed.

In the preferred embodiment of the present invention, the calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one half molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert water miscible organic solvent, at a temperature of from about 20 to about l00C.

In the preferred embodiment of the present invention, the aluminum salts of the acids are prepared by treating the acids with at least one third molar equivalent of an aluminum alkoxide, such as aluminum triethoxide, aluminum tripropoxide and the like, in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, and the like at a temperature of from about 20 to about I lC.

The starting compounds for use in the present invention are known and can be prepared in accordance with known procedures. Thus, the l,3-dicarbo(lower)alkoxy4-halobenzene starting compounds (2) are conveniently prepared by oxidizing l,3-dimethyl-4-halobenzene (4-halo-m-xylene) with potassium permanganate, as described above (31 32), followed by conventional esterification. The 0- or p-acylphenols (1) are conveniently prepared by performing a Friedel- Crafts reaction with phenol to give the desired acyl phenol compounds which can be separated such as by steam distillation. The acyl group thereof is reduced with platinum oxide or palladium catalyst in the presence of perchloric acid in ethanol. Lower alkoxyphenylcarboxylic acid chloride acylating agents for the preparation of alkoxyphenylcarbonylphenol starting compounds, are prepared, for example, by selectively esterifying hydroxybenzoic acid with methanol and a trace of sulfuric acid or with lithium carbonate and methyl halide in dimethylformamide. The resultant hydroxybenzoate ester is then conventionally alkylated with lower alkylhalide and potassium carbonate followed by selective hydrolysis of the ester of the carboxylic acid group and conversion to the acid chloride with, e.g. thionyl chloride.

in the present specification and claims, by the term 5 lower alkyl" is intended a lower alkyl group containing one to eight carbon atoms including straight and branched chain groups, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl, n-hexyl, npenl0 tyl, n-octyl, isooctyl. The term cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. By the term lower alkoxy" is intended the group 0- lower alkyl" wherein lower alkyl is as defined above. By the term "lower alkylthio" is intended the group S- [5 lower alkyl" wherein lower alkyl is as defined above. The term substituted phenyl includes p-substituted phenyl. The term monocyclic aromatic heterocyclic group includes pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidozolyl, furanyl, thiophenyl, 20 pyrrolyl, isoxazolyl, and oxazolyl.

By the term pharmaceutically acceptable, non-toxic esters, amides, and salts is respectively intended an alkyl or glycerol ester; an unsubstituted, monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl, or phenethyl substituted amide and a salt as defined above.

In the secondary and tertiary hydroxyalkyl series the compounds may possess a chiral center. The methods hereof generate each of the d and l and cll forms and each is thus included within the scope hereof. If desired, the isomers can be separated by conventional means such as forming the alkaloid salts of the products and employing fractional crystallization.

The nomenclature herein is employed in accordance with Chemical Abstracts 56 Subject Index (1962, January-June The following examples illustrate the method by which the present invention can be practiced.

EXAMPLE 1 A mixture of 3.9 g. of 1,3-dicarbomethoxy-4-bromobenzene, 2.85 g. of p-acetylphenol, 1.1 g. of cuprous oxide, and 25 ml. of tetramethylurea is heated to 165C and maintained thereat with stirring for 18 hours under a nitrogen atmosphere. After this time, the reaction mixture is diluted with water and extracted with ether. The extracts are dried and evaporated to give 1,3- dicarbomethoxy-4-(p-acetylphenyloxy)-benzene.

l ,3-Dicarbomethoxy-4-( p-acetylphenyloxy )-benzene (3.5 g.) is dissolved in 50 ml. of ethanol and the mixture treated with ml. of 4% aqueous potassium hydroxide solution. The reaction mixture is refluxed for 30 minutes, concentrated under reduced pressure, and acidified with dilute hydrochloric acid. The solid collected upon filtration is washed with water and dried to give 1,3-dicarboxy-4-(p-acetylphenyloxy)-benzene which is recrystallized from ethanol-water.

A solution of 3.2 g. of l.3-dicarboxy-4-(p-acetylphenyloxy)-benzene in 30 ml. of concentrated sulfuric acid is warmed to 80C. The mixture is then allowed to stand at room temperature for 16 hours after which time it is poured into ice water, filtered, washed and dried to give 7-acetylxanthone-2-carboxylic acid which is recrystallized from tetrahydrofuran-ethanol. The foregoing method can also be employed using an alternative 1,3-carboloweralkoxy-4-halo starting compound such as l,3-dicarbomethoxy-4-chloro or iodo benzene, 1,3-dicarboethoxy-4-fluoro benzene, 1,3-dicarboethoxy-4-bromo benzene, and the like, with similar results.

in a similar manner, the above described reactions can be conducted utilizing an alternate p-acyl phenol starting material to give the corresponding 7-acyl-xanthone-2-carboxylic acid products, e.g. 7-formylxa'nthone-2-carboxylic acid, 7-propionylxanthone-2-carboxylic acid, 7-n-butyrylxanthone-2-carboxylic acid, 7-isobutyrylxanthone-2-carboxylic acid, 7-n-pentanoylxanthone-2-carboxylic acid, 7-isopentanoylxanthone-Z-carboxylic acid, 7-sec-pentanoylxanthone-Z- carboxylic acid, 7-t-pentanoylxanthone-Z-carboxylic acid, 7-hexanoylxanthone-2-carboxylic acid, 7-heptanoylxanthone-2-carboxylic acid, 7-octanoylxanthone-Z-carboxylic acid, 7-nonanoylxanthone-2-carboxylic acid, 7-cyclopropylcarbonylxanthone-2-carboxylic acid, 7-cyclobutylcarbonylxanthone-Z-carboxylic acid, 7-cyclopentylcarbonylxanthone-2-carboxylic acid, 7-cyclohexylcarbonylxanthone-2-carboxylic acid, 7-haloacetylxanthone-2-carboxylic acid, 'l-benzoylxanthone-2-carboxylic acid, 7-substituted benzoylxanthone-Z-carboxylic acid, and 7-heterocycliccarbonylxanthone-2-carboxylic acid.

The procedure of Example 1 is repeated using the appropriate o-acyl phenol starting compounds to prepare the corresponding 5-substituted xanthone-2-carboxylic acid, to wit, 5-formylxanthone-2-carboxylic acid, 5- acetylxanthone-2-carboxylic acid, S-propionylxanthone-2-carboxylic acid, S-n-butyrylxanthone-Z-carboxylic acid, 5-isobutyrylxanthone-Z-carboxylic acid, and so forth.

EXAMPLE 2 To a solution of 25 grams of xanthone-Z-carboxylic acid (prepared as described in Example l from 1,3- dicarbomethoxy-4-bromobenzene and phenol) in 200 ml. of triethylene glycol are added 18 g. of potassium hydroxide and 12.1 g. of 95% hydrazine. The resultant mixture is heated to reflux (155C) and maintained thereat for 1 hour. The distillate is removed and the temperature is held at a temperature of about 200C for 2 hours. The mixture is then cooled to 68C and 200 ml. of water is added and the resultant solution poured into 1 10 m1. of water containing ml. of concentrated hydrochloric acid. The resultant mixture is heated to C, cooled to room temperature and filtered to give xanthene-Z-carboxylic acid.

26 Grams of xanthene-Z-carboxylic acid is added to 400 ml. of absolute methanol. To the resultant solution are added 18 ml. of concentrated sulfuric acid and the mixture is then heated at reflux for about 2 hours. The mixture is then cooled to 40C and sufficient water is added to bring the total volume to 1400 ml. The resultant mixture is then filtered to give methyl xanthene-2- carboxylate.

A mixture of 13.0 g. of methyl xanthene-2-carboxylate in 200 ml. of dichloroethane is cooled to -5C and to the cooled solution are added 4.95 ml. of acetyl chloride and then 17.0 g. of aluminum trichloride. The resultant solution is stirred at room temperature for 1.75 hours. After this time, the solution is poured into a mixture of 300 g. of ice, 700 ml. of water and 20 ml. of concentrated hydrochloric acid. The mixture is then extracted with three 500 ml. portions of methylene chloride. The combined extracts are washed with 10% aqueous potassium hydroxide solution and the washed solution evaporated to give methyl 7-acetylxanthene-2- carboxylate.

To a solution of 1.42 g. of methyl 7-acetylxanthene- Z-carboxylate in ml. of acetone and 15 ml. of di methylformamide are added 3.0 g. of magnesium sulfate and 2.5 ml. of 8N chromic acid in 8N sulfuric acid. The resultant mixture is stirred at room temperature for 50 minutes after which time a solution of 4 g. of sodium bisulfite in 20 ml. of water is added. After this time, 250 ml. of water and 25 ml. of sulfuric acid1water (1:1 are added. The mixture is stripped of solvent and filtered. The precipitate is washed with 50 ml. of water to give methyl 7-acetylxanthone-2-carboxylate which is recrystallized from methanol (displacement from methylene chloride solution).

A solution of 2 g. of methyl 7-acetylxanthone-2-carboxylate in 200 ml. of 10% aqueous, 10% potassium hydroxide in methanol is heated at reflux under a nitrogen atmosphere for 45 minutes. After this time, 20 ml. of water are added and the resultant mixture heated at reflux for 35 minutes. Water (300 ml.) is then added and the resultant mixture acidified and filtered to give 7-acetylxanthone-2-carboxylic acid.

EXAMPLE 3 The procedure of Example 2 is repeated employing, in the procedure of the third paragraph thereof, the acyl chlorides (prepared from the corresponding acids upon treatment with thionyl chloride or oxalyl chloride) listed in Column A below to prepare the corresponding acid products listed in Column B below, through their respective methyl esters.

Column A propionyl chloride n-butyryl chloride isobutyryl chloride n-pentanoyl chloride isopentanoyl chloride sec-pentanoyl chloride Column B cyclopropylcarbonyl chloride cyclohulylcarbonyl chloride cyclopentylcarhonyl chloride cyclohexylcarhonyl chloride trifluoroacetyl chloride dil'luoroacetyl chloride trichloroacctyl chloride dichloroacetyl chloride hcnzoyl chloride p-chlorohenzoyl chloride 7cyclopropylcarhonylxanthone-Z- carhoxylic acid 7-cyclohutylcarhonylxanthone-Z- carhoxylic acid 'lcyclopentylcarhonylxanthnne-2- carhoxylic acid 7-cyclohexylcarbonylxunthone-2 carboxylic acid 7-tril'luoroacetylxanthone-Z-carhoxylic acid 7-difluoroacetylxanthone 2-carhoxylic acid 7-triehloroacetylxanthone-Z-carboxylic acid 7-dichloroacetylxanthene-Z-earbnxylic acid 7-benzoylxanthone-Z-carboxylic acid 7-( p-chlorobenzoyl )xanthone-2-car hoxylic acid 7-[ p-methylhenzoyl xanthone-Z-carhoxylic acid 7-( p-methoxyhenzoyl )xanthone- 2- p-methylhcnzoyl chloride p-mcthoxybenzoyl chloride carboxylic acid pthiornethoxyhenzoyl 7-( p-thiomethoxybenzoyl )xanlhone-2- chloride carhoxylic acid furoyl chloride pyrmyl chloride thenoyl chloride pyridylcarhonyl chloride 7-furoylxanthone-2-carboxylic acid 7-pyrroylxanlhonc2 carboxylic acid 7-thenoylxanthone-2-carhoxylic acid 7-pyridylcarhonylxanthonc-2-carboxylic acid im idazolylcarhonyl 7- imidazolylcarbon ylxanthoneQ-carchloride boxylic acid oxazolylcarbonyl 7-oxazolylcarhonylxanthone-2-carboxylic chloride acid The foregoing is practiced using the corresponding acyl bromide starting compounds, with similar results.

EXAMPLE 4 A mixture of L077 g. of methyl 7-acetylxanthone-2- carboxylate, 200 mg. of sodium borohydride and 150 ml. of tetrahydrofuran is stirred for 2.5 hours at room temperature. The reaction is monitored by tlc. After this period of time, a 5% aqueous acetic acid solution is added to the reaction mixture dropwise to neutrality and the resultant solution evaporated under vacuum and crystallized by the addition of ethanol and hot water. The precipitate is filtered off, washed and dried to give methyl 7-(l-hydroxyethyl)-xanthone-2-carboxylate.

A mixture of 860 mg. of methyl 7-( l-hydroxyethyl)- xanthone-Z-carboxylate, 60 ml. of ethanol and 2 ml. of 2N sodium hydroxide is refluxed for minutes. The resultant mixture is cooled, acidified and the precipitate is filtered off, washed, and dried to give 7-(lhydroxyethyl )-xanthone-2-carboxylic acid.

The foregoing procedure are practiced upon the other 7-acyl methyl esters prepared as described in Example 3 to give the following products, through their respective methyl esters:

7-( l-hydroxy-n-propyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-butyl)-xanthone-2-carboxylic acid,

7-( l-hydroxyisobutyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-isopentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-sec-pentyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-t-pentyl)xanthone-2-carboxylic acid,

7-( l-hydroxy-n-hexyl)-xanthone-2-carboxylic acid,

7-( 1-hydroxy-n-heptyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid,

7-( l-hydroxy-n-nonyl)-xanthone-2-carboxylic acid,

7-( cyclopropyl )hydroxymethyl )-xanthone-2-carboxylic acid,

7-( cyclobutyl )hydroxymethyl)-xanthone-2-carboxylic acid,

7-((cyclopentyl)hydroxymethyl)-xanthone-2-carboxylic acid,

7-( cyclohexyl )hydroxymethyl)-xanthone-2-carboxylic acid,

7-( 2,2,2-trifluorol -hydroxyethyl )-xanthone-2-carboxylic acid,

7-(2,2-difluoro-1-hydroxyethyl)-xanthone-2-carboxylic acid,

7-( 2 ,2,2-trichlorol-hydroxyethyl)-xanthone-2-carboxylic acid,

7-( 2,2-dichlorol -hydroxyethyl)-xanthone-2-carboxylic acid,

7-( phenyl )hydroxymethyl )-xanthone-2-carboxylic acid,

7-((p-chlorophenyl)hydroxymethyl)-xanthone-2- carboxylic acid,

'7-( p-methylphenyl )hydroxymethyl )-xanthone-2- carboxylic acid,

21 7-( (p-methoxyphenyl )hydroxymethyl)-xanthone-2- carboxylic acid, '7-((p-thiomethoxyphenyl)hydroxymethyl)-xanthone-Z-carboxylic acid,

22 7-( l-hydroxyl methyl-n-heptyl )-xanthone-2-car boxylic acid, 7-( l-hydroxyl -methyl-n-octyl )-xanthone2-carboxylic acid,

7-((furyl )hydroxymethyl)-xanthone-2-carboxylic 7-( l-hydroxy-l-methyl-n-n0nyl)-xanthone-2-caracid, boxylic acid, 7-( (pyrryl )hydroxymethyl )xanthone-2-carboxylic 7-( l -hydroxy-1-cyclopropylethyl)xanthone-2-caracid, boxylic acid, 7-( thienyl )hydroxymethyl )-xanthonc-2-carhoxy1ic 7-( l -hydroxy- 1 -cyclobuty1ethyl)-xanthone-2-caracid, boxylic acid, 7-( pyridyl )hydroxymethyl )xanthone-2-carboxylic 7-( l -hydroxyl -cyclopentylethyl)-xanthone-2-caracid, boxylic acid, 7-( (imidazolyl )hydroxymethyl )-xanthone-2-car- 7-( l-hydroxyl -cyclohexylethyl )-xanthone-2-carboxylic acid, boxylic acid, 7-((oxazolyl)hydroxymethyl)manthone-Z-carboxylic 7-( l-hydroxy-l-trifluoromethylethyl)-xanthone-2- acid. carboxylic acid,

7( l -hydroxyl -difluoromethylethyl )-xanthone-2 EXAMPLE 5 carboxylic acid, A solution of 4.] g. of methyl 7-acetylxanthone-2- 7-(l-hydroxy-l-trichloromethylethyl)-xanthone-2- carboxylate in 120 ml. of tetrahydrofuran is stirred at carboxylic acid, 0C and 6.8 ml. of 3M methylmagnesium bromide solu- 7-( l-hydroxy-l-dichloromethylethyl )-xanthone-2- tion in ether are added dropwise. After stirring at 0C carboxylic acid, for 30 minutes, the reaction mixture is left to warm up 7-( l-hydroxy-l-phenylethyl)-xanthone-2-carboxylic to room temperature. A saturated ammonium chloride acid, solution (50 ml,) is then added and the mixture is con- 7-( l-hydroxy-1-p-chlorophenylethyl)-xanthone-2' centrated in vacuo. Extraction with ethyl acetate folcarboxylic acid, lowed by evaporation yields methyl 7-(1-hydroxy-l- 7-( l-hydroxy-l-p-methylphenylethyl)-xanthone-2- methylethyl)-xanthone-2-carboxylate. Hydrolysis procarboxylic acid, vides 7-( l-hydroxy-l-methylethyl)-xanthone-2-car- 7-( l-hydroxy-l-p-methoxyphenylethyl)-xanthone-2- boxylic acid. carboxylic acid,

The foregoing procedure is practiced upon the other 7-( l-hydr0xy-l-p-thiomethoxyphenylethyl)-xan- 7-acryl methyl esters prepared as described in Example thone-2-carboxylic acid, 3 to give the following products, through their respec- 7-( l-hydr0xy-l-furylethyl)-xanthone-2-carboxylic tive methyl esters: acid,

7-( l-hydroxyl -methyl-n-propyl)-xanthone-2-car- 7( l-hydroxyl -pyrrylethyl)-xanthone-2-carboxylic boxylic acid, acid, 7-( ]-hydroxyl -methyl-n-butyl )-xanthone-2-car- 7-( l-hydroxyl -thienylethyl )-xanthone-2-carboxylic boxylic acid, acid, 7-( l-hydroxyl -methyl-is0butyl )-xanthone-2-car 7-( l -hydroxyl -pyridylethyl)-xanthone-2-carboxylic boxylic acid, acid, 7-( l-hydroxy-l -methyl-n-pentyl )-xanthone-2-car- 7-( l-hydroxyl -imidazolylethyl )-xanthone-2-carboxylic acid, boxylic acid, 7-( l-hydroxy-l -methyl-isopentyl )-xanthone2-car- 7( l-hydroxy-l -oxazolylethyl )-xanthone-2-carboxyboxylic acid, 4 lic acid. 7-( l-hydroxy-l-methyl-sec-pentyl)-xanthone-2-car- 5 EXAMPLE 6 boxylic acid, 7-( l-hydroxy-1-methylt-pentyl)-xanth0ne-2-car- The procedure of Example 5 is repeated employing, b li id, in lieu of methyl magnesium bromide, the reagents 7-( l-hydroxy-1-methyl-n-hexyl)-xanthone-2-carlisted in Column C below to prepare the products listed boxylic acid, in Column D below.

Column C Column D ethylmagnesium bromide n-propylmagnesium bromide isopropylmagnesium bromide n-butylmagnesium bromide -continued Column C Column D isohutylmagnesium bromide sec-butylmagnesium bromide t-butylmagnesium bromide n-pentylmagnesium bromide hexylmagnesium bromide heptylmagnesium bromide octylmagnesium bromide cyclopropylmagncsium bromide cyclobutylmagncsium bromide cyclopentylmagnesium brom id c cyclohcxylmagnesium bromide 7-( l-hydroxyl -isobutylethyl xanthone-Z-curboxylic acid.

7-( l-hydroxy-l -isobutyl-n-propyl xanthonc-Z-carboxyiic acid.

and so forth.

7-( l-hydroxyl -sec-hutylcthyl xunthone-Z-carboxylic acid.

7-( l-hydroxyl -sec-hutyLn-propyl xunthone-Z-carhoxyiic acid.

and so forth.

7-( l-hydroxyl -t-hutylethyl xanthone-Z-carboxylic acid.

7-( l-hydroxyl -t-hutyl-n-propyl xanthone-Z-carhoxylic acid.

and so forth.

7-( l-hydroxy-l-n-pentylcthyhxanthone-2-carboxylic acid.

7-( l-hydroxyl -n-penlyl-n-propyl)- xanthone-2-carboxylic acid.

and so forth.

7-( 1 -hydroxyl -hexylethyl )-xunthone- Z-carboxylic acid,

7-( l -hydrnxy-l-hexyl-n-prpyl)- xanthone-Z-carboxylic acid.

and so forth.

7-( l-hydroxyl -heptylethyl xanthone-Z-carboxylic acid.

7-( l -hydroxyl -heptyl-n-pr0pyl xanthone-Z-carboxylic acid.

and so forth.

7( l-hydroxyl -oclylelhyl )-xanthone- Z-carhoxylic acid,

and so forth.

7-( l-hydroxyl -cyciopropylethyl xanlhone2-carboxylic acid,

7-( l -hydroxy-1 -cyclopropyl-n-propyl)- xanlhone-Z-carhoxylic acid.

and so forth.

7-( l-hydroxyl -cyclobutylethyl xanlhone-2carboxylic acid.

7( lhydroxy-l -cyclobutyl-n-propyl xanthone-2-carboxylic acid.

and so forth,

7-( l-hydroxy l -cyclopentylethyl xunthone-Z-carhoxylic acid.

7-( l-hydroxy- 1 -cyclopentyl-n-propyl xanlhone-Z-carboxylic acid,

and so forth.

7-( l-hydroxyl -cyclohcxylethylxanlhone-Z-carboxylic acid,

7-( l-hydroxy l -cyclohexyl-n-propyl xanthone-Z-carboxylic acid.

and so forth.

EXAMPLE 7 A mixture of methyl xanthene-Z-carboxylate (5.1 g),

7.0 g. of aluminum chloride, 3 g. of chloroacetyl chloride. and 100 ml. of dichloroethane is stirred at room temperature for 4 hours. After the addition of hydrochloric acid-ice followed by chloroform extraction, the mixture is filtered through alumina (Cl- 0 and evaporated to give methyl 7-chloroacetylxanthene-2- carboxylate.

The thus-prepared compound is oxidized according to the procedure of the fourth paragraph of Example 2 to give methyl 7-chloroacetylxanthone-2-carboxylate.

A mixture of 750 mg. of methyl 7-chloroacetylxanthone2-carboxylate, 200 mg. of sodium borohydride, and 75 ml. of tetrahydrofuran is stirred for 1 hour at room temperature. Tlc (CH Cl,/AcOEt 9:l) indicates the reaction is complete. Excess sodium borohydride is destroyed by the dropwise addition of aqueous acetic acid The mixture is concentrated in vacuo and extracted with ethyl acetate to give methyl 7-( lhydroxy-Z-chloroethyl )-xanthone-2-carboxylate.

A mixture of 750 mg. of methyl 7-(l-hydroxy-2- chloroethyl)-xanthone-2-carboxylate. l50 mg. of sodium hydride, ml. of dimethylformamide is stirred for 3 hours at room temperature. Excess sodium hydride is destroyed by adding a few drops of acetic acid. The mixture is then diluted with water, extracted with ethyl acetate and chromatographed on 75 g. of silica (CH Cl /AcOEt: 9:l) to give methyl 7-(l,2-oxidoethyl )-xanthone-2-carboxylate.

A mixture of I I3 mg. of methyl 7-( l,2-oxidoethyl)- xanthone-Z-carboxylate, 100 mg. of periodic acid, and I5 ml. of tetrahydrofuran is stirred at room temperature for 2 hours. After this time, 15 ml. of methylene chloride is added, the mixture filtered through alumina (CH CI and evaporated. The residue is crystallized from methylene chloridezmethanol to give methyl 7- formylxanthone-Z-carboxylate.

A mixture of 1.2 g. of methyl 7-formylxanthone-2- carboxylate, 10 ml. of 2N sodium hydroxide, and ml. of ethanol is refluxed for 60 minutes. Then, it is acidified, cooled. and suction filtered to give 7 -for mylxanthone-2-carboxylic acid.

Reduction thereof as described in the first paragraph of Example 4 gives 7-hydroxymethylxanthone-2-carboxylic acid.

Employing methyl 5-chloroacetylxanthene-2-carboxylate, prepared as described above, in the above procedure, affords S-formylxanthone-2-carboxylic acid which can be reduced to S-hydroxymethylxanthone-2- carboxylic acid.

EXAMPLE 8 5-Ethylxanthone-Z-carboxylic acid is prepared from l,3-dicarbomethoxy-4-bromobenzene and o-ethylphenol in accordance with the procedures set forth in Example 1 above.

A mixture of 4 g. of the thus-obtained 5-ethylxanthone-2-carboxylic acids, l g. of methyl iodide, and I0 g. of potassium carbonate in 50 ml. of dimethylformamide is stirred at room temperature for a period of 16 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant mixture extracted with ethyl acetate. The extracts are filtered through alumina to give methyl ethylxanthone-2-carboxylate which can be recrystallized from methanol.

A suspension of 2.5 g. of methyl 5-ethylxanthone-2 carboxylate and 2.5 g. of chromic oxide in 190 ml. of acetic acid and ml. of acetic anhydride is stirred at room temperature for a period of 6 hours. After monitoring the reaction by tlc indicates the absence of starting material, 10 ml. of isopropanol are added and the resultant mixture warmed on the steam bath. Water (200 ml.) is then added portionwise to the resultant mixture is cooled to room temperature. The precipitate is filtered off, washed, and dried to obtain methyl 5- acetylxanthone-Z-carboxylate.

A mixture of 1.09 g. of methyl S-acetylxanthone-Z- carboxylate, 70 ml. of isopropanol, 5 ml. of saturated sodium carbonate solution, and 25 ml. of water is refluxed for two hours. The resultant mixture is then acidified, cooled and the crystals filtered off, washed, and dried to give 5-acetylxanthone-2-carboxylic acid.

The foregoing procedures can be followed with other S-substituted methyl compounds (prepared according to the procedures of Example I) to give the corresponding S-acyl compounds, to wit:

5-propionylxanthone-2-carboxylic acid;

5-n-butyrylxanthone-2-carboxylic acid; 5-isobutyrylxanthone-Z-carboxylic acid;

S-n-pentanoylxanthone-Z-carboxylic acid;

5-isopentanoylxanthone-2-carboxylic acid;

5-sec-pentanoylxanthone-2-carboxylic acid; 5-t-pentanoylxanthone2-carboxylic acid;

S-n-hexanoylxanthone-2-carboxylic acid;

5-n-heptanoylxanthone-2-carboxylic acid;

5-n-octanoylxanthone-2-carboxylic acid; 5-n-nonanoylxanthone-Z-carboxylic acid; 5-cyclopropylcarbonylxanthone-Z-carboxylic acid; 5-cyclobutylcarbonylxanthone-2-carboxylic acid; 5-cyclopentylcarbonylxanthone-Z-carboxylic acid; 5-cyclohexylcarbonylxanthonee-Z-carboxylic acid; 5-trifluoroacetylxanthone-2-carboxylic acid;

S-difluoroacetylxanthone-Z-carboxylic acid;

5-trichloroacetylxanthone-2-carboxylic acid;

S-dichloroacetylxanthone-Z-carboxylic acid;

5-benzoylxanthanone-Z-carboxylic acid;

5-(p-chlorobenzoyl)-xanthone-2-carboxylic acid; 5-(p-methylbenzyl)-xanthone-2-carboxylic acid;

5-( p-methoxybenzoyl )-xanthone-2-carboxylic acid;

S-(p-thiomethoxybenzoyl )-xanthone-2-carboxylic acid; 5-furoylxanthone-Z-carboxylic acid; S-pyprroylxanthone-Z-carboxylic acid; 5-thenoxyxanthone-2-carboxylic acid; 5-pyridylcarbonylxanthone-Z-carboxylic acid; 5-imidazolylcarbonylxanthone-2-carboxylic acid; 5-oxazolylcarbonylxanthone-2-carboxylic acid.

EXAMPLE 9 Methyl 5-acetylxanthone-2-carboxylate is treated in accordance with the procedure of the first paragraph of Example 4, to give methyl 5-( l-hydroxyethyl)-xanthone-2-carboxylate which is hydrolyzed in accordance with the second paragraph thereof to give 5-( lhydroxyethyl)-xanthone-2-carboxylic acid.

The foregoing procedures can be followed with other S-acyl methyl esters prepared as described in Example 8 to give the corresponding 5-( l-hydroxyalkyl) compounds through their methyl esters, to wit:

5-( l-hydroxy-n-propyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-butyl)-xanthone-2-carboxylic acid;

5-( l-hydroxyisobutyl)-xanthone-2-carboxylic acid;

( l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid;

( l-hydroxyisopentyl)-xanthone-2-carboxylic acid;

( l-hydroxy-sec-pentyl-xanthone-2-carboxylic acid;

( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid;

( l -hydroxy-n-heptyl)-xanthone-2-carboxylic acid;

5-( l-hydroxy-n-heptyl)-xanthone-2-carboxylic acid;

S-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid;

5-( l -hydroxy-n-nonyl )-xanthone-2-carboxylic acid;

5-((cyclopropyl)hydroxymethyl)-xanthone-2-carboxylic acid;

5-( cyclobutyl )hydroxymethyl )-xanthone-2-carboxylic acid;

5-((cyclopentyl)hydroxymethyl)-xanthone-2-carboxylic acid;

5-((cyclohexyl)hydroxymethyl)-xanthone-2-carboxylic acid;

5-( 2 ,2,2-trifluorol -hydroxyethyl )-xanthone-2-carboxylic acid;

5-( 2 ,2-difluoro-l -hydroxyethyl )-xanthone-2-carboxylic acid;

5-( 2 ,2,2-trichlorol -hydroxyethyl )-xanthone-2-carboxylic acid;

5-( 2,2-dichlor0- l -hydroxyethyl )-xanthone-2-carboxylic acid;

5-((phenyl)hydroxymethyl)-xanthone-2-carboxylic acid 5-((p-chlorophenyl)hydroxymethyl)-xanthone-2- carboxylic acid;

5-( p-methylphenyl )hydroxymethyl)-xanthone-2- carboxylic acid;

5-((p-methoxyphenyl)hydroxymethyl)-xanthone-2- carboxylic acid;

5-( p-thiomethoxyphenyl )hydroxymethyl )-xanthone-2-carboxylic acid;

5-( fury] )hydroxymethyl )-xanthone-2-carboxylic acid;

5-( pyrryl )hydroxymethyl )-xanthone-2-carboxylic acid;

5-( (thienyl hydroxymethyl )-xanthone-2-carboxylic acid;

5-((pyridyl)hydroxymethyl)-xanthone-2-carb0xylic acid;

5-((imidazolyl)-xanthone-2-carboxylic acid;

5-( (oxazoyl )hydroxymethyl )-xanthone-2-carboxylic acid.

-continued Column C Column D hexylmagnesium bromide heptylmagnesium bromide octylmagnesium bromide S-( l-hydroxyl -octyl-n-propyl xanthone-Lcarboxylic acid.

and so forth.

-( I-hydroxy-l-cyclopropylethyl)- xanthone-Z-carbnxylic acid.

5( l-hydroxy-l-cyclopropyl-n-propyljlxanthone-Z-curboxylic acid.

and so forth.

5-( l-hydroxyl -cyclobutylelhyl xanlhone-Z-carhoxylic acid.

5( Lhydroxyl -cyclobutyl-n-propyl xanthone-2carhoxylic acid.

and so forth.

5% l-hydroxy l -cyclopentylethyl xanthone2-carboxylic acid.

5 l-hydroxyl -cyclopentyl-n-propyl)- xanlhone 2 carhoxylic acid.

and so forth.

5( l hydroxy l -cyclohexylethyl xanthone-Z-carboxylic acid 54 Lhydroxyl -cyclohexyln-propyl)- xanthone-Z-carboxylic acid.

and so forth.

cyclopropylmagnesium bromide cyclohutylmagncsium bromide cyclopentylmagnesium bromide cyclohcxylmagnesium bromide EXAMPLE l2 Methyl-5-methylxanthone-Z-carboxylate is prepared by the procedure of Example 1 from o-methylphenol, followed by the preparation of the methyl ester of the thus-produced acid.

To a solution of2.4 g. of methyl S-methylxanthone-Z carboxylate in 30 ml. acetic acid and 30 ml. acetic anhydride are added 4.8 ml. concentrated sulfuric acid at 0C. After the addition of 5.6 g. of chromic acid, the mixture is stirred for five hours. The crude diacetoxymethyl intermediate is isolated by diluting the reaction mexture with water and filtering off the precipitate. The formyl derivative is obtained by refluxing the diacetoxymethyl compound thus obtained with ml. 2N sulfuric acid in 90 ml. methanol for minutes, cooling. diluting with 60 ml. water and filtering off the precipitate to give 5-formylxanthone2-carboxylic acid. This compound can be reduced as described above to S-hydroxymethylxanthone-Z-carboxylic acid.

7-Formylxanthone Z-carboxylic acid is prepared by the above procedure. preferably by using 30 ml. of 2N sulfuric acid in 70 ml. of ethanol for 2 hour treatment of the diacetate.

EXAMPLE 13 A mixture of 51.5 g. of 1,3-dimethyl-4 iodobenzene (4-iodo-m-xy1ene), g. of o-formylphenol. 16 g. of cuprous oxide in 300 m1. of dimethylacetamide is heated to the boiling point and maintained under reflux (190C) for 144 hours with stirring and under a nitrogen atmosphere. The reaction mixture is then poured into ice water and extracted with ether and the extracts are filtered through 500 g. of alumina in hexane to give l,3-dimethyl-4-o-formy1pheny1oxy)-benzene.

A mixture of 41 g. of l,3-dirnethyl-4-(o-formylphenyloxy)-benzene. 300 g. of potassium permanga nate, 500 m1. of t-butanol, and 750 m1. of water is heated to the boiling point and maintained thereat for a period of three. hours. After distilling off the t butanol. the reaction mixture is filtered, the clear filtrate acidified and the precipitate of 1.3-dicarboxy-4- (o-formylphenyloxy)-benzene is isolated by suction filtration and washed with water.

The l,3-dicarboxy-4-(o-formylphenyloxy )-benzene thus prepared is then cyclized as described in Examples 1 or 14 to give 5-formylxanthone-2-carboxylic acid.

In like manner. the other C-5 and -7-substituted xan' thone-Z-carboxylic acid compounds hereof are prepared. These compounds can then be treated as described in Examples 4 to 6 and 8 to ll to prepare the corresponding C-5 and -7-substituted compounds.

EXAMPLE 14 A mixture of 2.84 ml. of o'ethylphenol, 5.0 g. of 1,3- dicarbomethoxy-4-bromobenzene and 1.31 g. of cuprous oxide in ml. of dimethylacetamide is stirred under reflux overnight. The resultant mixture is then poured on ice and extracted with ether. The ether ex tracts are washed with water and 2N aqueous sodium hydroxide. The washed extracts are dried and evaporated to give l,3-dicarbomethoxy-4-(o-ethylphenyloxy)-benzene which can be purified by chromatography through alumina with gradient elution with benzene:- hexane (50:50 60:40).

A mixture of 24 g. of l.2-dicarbomethoxy-4 (o-ethylphenyloxy)-benzene, 20 g. of potassium hydroxide, 300

31 ml. of ethanol and 20 ml. of water are heated on a steam bath for about V: hour. After this time, the reaction mixture is acidified with dilute hydrochloric acid and the ethanol evaporated. The resultant mixture is then extracted with ethyl acetate and the extracts are dried and evaporated to give l,3-dicarboxy-4-(o-ethylphenyloxy)-benzene which can be crystallized from methanolzethyl acetate.

A mixture of 1.94 g. of l,3-dicarboxy-4-(o-ethylphenyloxy)-benzene, 40 ml. of sulfolane and 30 ml. of polyphosphoric acid is stirred at l60C for 30 minutes. The resultant mixture is then diluted with water and the diluted mixture filtered. The precipitate is washed neutral, and then dissolved and heated in ethanol containing charcoal. The resultant mixture is then filtered, and the ethanol is partially evaporated. Water is added until crystalline starts. Filtration gives the solid product 5- ethylxanthone-Z-carboxylic acid which can be recrystallized from ethanol.

The foregoing product is useful as described in Example 8 et seq.

In like manner, the foregoing reactions can be conducted using an alternate l,3-dicarboalkoxy-4-halobenzene starting material such as 1,3-dicarboxy-4- bromobenzene, l,3-dicarboethoxy-4-iodobenzene, and so forth, with similar results.

Upon substituting the other phenol starting compounds in the process of the preceding example, there are obtained the corresponding C-5 and C-7 substituted xanthone-2-carboxylic acids.

EXAMPLE To a solution of 6 g. of methyl 7-acetylxanthene-2- carboxylate in 500 ml. of absolute methanol are added 1.1 g. of sodium borohydride in 50 ml. of water at a temperature of from 25 to 30C with stirring, over a period of about 30 minutes. After 15 minutes under these conditions, 400 ml. of water and ml. of acetic acid are added and the resultant mixture is stripped of solvent. The resultant mixture is extracted with methy lene chloride and washed with bicarbonate and water. The washed extracts are concentrated to give methyl 7-( l-hydroxy-ethyl)-xanthene-2-carboxylate.

A solution of 5.5 g. of methyl 7-(l-hydroxyethyl)- xanthene-2-carboxylate in lOO ml. of pyridine is cooled in an ice bath. To the cooled solution are added 2.91 ml. of acetyl chloride and the resultant mixture is stirred in an ice bath for k hour and then at room temperature for l hour. After this time, the reaction mixture is poured into dilute hydrochloric acid-ice and the precipitate is filtered off and washed to give methyl 7- l -acetoxyethyl)-xanthene-2-carboxylate.

To a solution of 3 g. of methyl 7-( l-acetoxyethyl)- xanthene-Z-carboxylate in 80 ml. of acetone are added 12 ml. of 8N chromic acid in 8N sulfuric acid. The resultant mixture is stirred at room temperature for l 54 hours. Excess chromic oxide is decomposed with aqueous sodium bisulfite and to the resultant mixture are added 500 ml. of water. The resultant mixture is stripped of solvent and extracted with methylene chloride. The methylene chloride extracts are washed with 10% aqueous sodium bicarbonate solution and the washed extracts are concentrated in vacuum to give methyl 7-( l-acetoxyethyl)-xanthone-2-carboxylate.

A solution of 2.70 g. of methyl 7-( l-acetoxyethyl)- xanthone-Z-carboxylate in 300 ml. of a 10% potassium hydroxide 10% aqueous methanol solution is heated under reflux under a nitrogen atmosphere for a period 32 of 1 hour. After this time, 40 ml. of concentrated hy drochloric acid in ml. of water are added. Thereafter, ml. of water are added and the resultant solution is stripped of solvent in vacuum and filtered to give 7-( l-hydroxyethyl )-xanthone-2-carboxylic acid.

In like manner, by subjecting the other 7-acyl or 5- acyl xanthone-Z-carboxylic compounds as described in Examples 1 to 3 and 8 above to the procedure of the present example, the corresponding (l-hydroxyalkyl)- xanthone2-carboxylic acid compounds are prepared.

EXAMPLE 16 A mixture of 2 g. of 7-(l-hydroxyethyl)-xanthone-2- carboxylic acid in 8 ml. of pyridine and 4 ml. of acetyl chloride is heated at steam bath temperature for one hour. The mixture is then poured into HCl/ice water and the solid which forms is collected by filtration, washed with water and dried to yield 7-( l-acetoxyethyl)-xanthone-2-carboxylic acid.

in a similar manner, 5-( l-acetoxyethyl)-xanthone'2- carboxylic acid is prepared.

Upon substitution of the appropriate acyl chloride in the above procedure and, in addition, employing as starting compounds the products listed in Examples 4 and 9, the following compounds are prepared:

7-( l-propionyloxyethyl)-xanthone-2-carboxylic acid,

5-( l-propionyloxyethyl)-xarithone-2-carboxylic acid,

7-( l-butyryloxyethyl)-xanthone-2-carboxylic acid.

5-( l -butyryloxyethyl )-xanthorie-2-carboxylic acid,

7-( l-acetoxy-n-propyl)-xanthone-2-carboxylic acid,

5-(l-acetoxy-n-propyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-acetoxy-n-butyl)-xanthone-2-carboxylic acid,

5-( l-acetoxynbutyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-acetoxyisobutyl)-xanthone-2-carboxylic acid,

5-( l-acetoxyisobutyl)-xanthone-2-carboxylic acid,

and so forth,

7-( (cyclopropyl )acetoxymethyl )-xanthone 2-carboxylic acid,

5-( cyclopropyl )acetoxymethyl )-xanthone-2-carboxylic acid, and so forth,

7-( phenyl )acetoxymethyl )-xanthone-2-carboxylic acid, 5-((phenyl)acetoxymethyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE l7 A mixture of 2 g. of 7-(l-hydroxy-l-methylethyl)- xanthone-Z-carboxylic acid, l5 ml. of tetrahydrofuran, 5 ml. of dimethylaniline, and 5 ml. of acetyl chloride is refluxed for six hours. The mixture is then concentrated in vacuo to remove a portion of the tetrahydrofuran. Dilute HCl is added, the mixture is filtered, washed and dried to give 7-( l-acetoxy-l-methylethyl)- xanthone-2-carboxylic acid.

In a similar manner, 5-( l-acetoxy-l-methylethyl)- xanthene-Z-carboxylic acid is prepared.

Upon substitution of the appropriate acyl chloride in the above procedure and, in addition, employing as starting compounds the products listed in Examples 5, 6, l0 and l l, the following compounds are prepared:

7-( l-acetoxyl-methyl-n-propyl )-xanthone-2-carboxylic acid,

7-( l-acetoxylmethyl-isobutyl )-xanthone-2-carboxylic acid,

7-( l-propionyloxyl -methyl-n-propyl )-xanthone-2- carboxylic acid,

EXAMPLE [8 To a mixture of 2.5 g. of methyl 7-( l-hydroxyethyl)- xanthone-Z-carboxylate and 500 mg. of sodium hydride in 45 ml. of dimethylformamide is added 2 ml. of methyl iodide and the mixture is stirred at room temperature for 16 hours. The mixture is then poured into dilute HCl/ice water, filtered and dried to give methyl 7-( l-methoxyethyl)-xanthone-2-carboxylate.

The resultant product is hydrolyzed according to the procedure of Paragraph 2 of Example 1 to give 7( lmethoxyethyl)-xanthone-2-carboxylic acid.

In a similar manner, 5-( l-methoxyethyl)-xanthone-2- carboxylic acid is prepared.

Upon substitution of the appropriate alkyl or cycloalkyl iodide or bromide and, in addition, employing as starting compounds the products listed in Examples 4 and 9. the following compounds are prepared, through their respective esters:

7-( l-ethoxyethyl)-xanthone-2-carboxylic acid,

5-( l-ethoxyethyl)-xanthone-2-carboxylic acid,

7-( 1-n-propoxyethyl)-xanthone-2-carboxylic acid,

5-( 1-npropoxyethyl)-xanthone-2-carboxylic acid,

7-( l-isopropoxyethyl)-xanthone-2-carboxylic acid,

S-( l-isopropoxyethyl)-xanthone-2-carboxylic acid,

7-( l-cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

5-( l-cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

7-( l-methoxy-n-propyl)-xanthone-2-carboxylic acid,

5-( l-methoxy-n-propyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-methoxy-n-butyl)-xanthone-2-carboxylic acid,

5-( 1-methoxy-n-butyl)-xanthone-2-carboxylic acid,

and so forth,

7-( l-methoxyisobutyl)-xanthone-2-carboxylic acid,

5-( l-methoxyisobutyl )-xanthone-2-carboxylic acid,

and so forth,

7-( cyclopropyl )methoxymethyl )-xanthone-2-carboxylic acid,

5-((cyclopropyl)methoxymethyl)-xanthone-2-carboxylic acid, and so forth,

7-( phenyl )methoxymethyl )-xanthone-2-carboxylic acid,

5-( (phenyl )methoxymethyl )-xanthone-2-carboxylic acid, and

7-( l-methoxyl-methylethyl )-xanthone-2-carboxylic acid,

5-( l -methoxyl -methylethyl )-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 19 A solution of 4.1 g. of methyl 7-acetylxanthone-2- carboxylate in ml. of tetrahydrofuran is stirred at 0C and 6.8 ml. of 3M methylmagnesium bromide solution in ether are added dropwise. After stirring at 0C for 30 minutes, 2 ml. of methyl iodide and 30 ml. of hexamethylphosphoramide are added and the mixture is stirred at room temperature for 5 hours. A saturated ammonium chloride solution (50 ml.) is then added and the mixture is concentrated in vacuo. Extraction with ethyl acetate followed by evaporation yields methyl 7-( l-methoxyl -methylethyl)-xanthone-2-carboxylate. Hydrolysis provides 7-( l-methoxy-lmethylethyl)-xanthone-2-carboxylic acid.

Likewise, 5-( l-methoxyl-methylethyl)-xanthone-2- carboxylic acid is prepared.

Upon substituting the appropriate alkyl or cycloalkyl bromide and, in addition, using the other starting materials listed in Examples 3 and 8, the following compounds are prepared:

7-( l-ethoxyl-methylethyl)-xanthone-2-carboxylic acid,

5-( l-ethoxyl-methylethyl)-xanthone-2-carboxylic acid,

7-( l-propoxyl -methylethyl )-xanthone-2-carboxylic acid,

5-( l-propoxyl -methylethyl)-xanthone-2-carboxylic acid,

7-( l-cyclopentyloxyl -methylethyl )-xanthone-2-carboxylic acid,

5-( l-cyclopentyloxyl-methylethyl )-xanthone-2-carboxylic acid,

7-( l-methoxyl-methyl-n-propyl )-xanthone-2-carboxylic acid,

5-( l -methoxyl-methyl-n-propyl)-xanthone-2-carboxylic acid, and so forth,

7-( l-methoxyl -rnethyl-isobutyl)-xanthone-2-carboxylic acid,

5-( l-methoxy-l-methyl-isobutyl)-xanthone-2-carboxylic acid, and so forth,

7-( l-methoxyl-cyclopentylethyl)-xanthone-2-carboxylic acid,

S-( l-methoxyl-cyclopentylethyl)-xanthone-2-carboxylic acid, and so forth,

7-( l-methoxyl-phenylethyl)-xanthone-2-carboxylic acid,

5-( l-methoxyl -phenylethyl)-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 20 A mixture of 1.6 g. of methyl 7-( l-hydroxyethyl)- xanthone-2-carboxylate, 50 ml. of methylene chloride, 50 ml. of isobutene and 2 ml. of BF /H PO catalyst are shaken in a pressure bottle for 4 days at room temperature. The reaction mixture is diluted with methylene chloride, washed with bicarbonate solution, then water, dried and evaporated and crystallized from methanol to give methyl 7-( l-t-butoxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides 7-( l-t-butoxyethyl,)-xanthone-2- carboxylic acid.

Likewise, 5-(1-t-butoxyethyl)-xanthone-2-carboxylic acid is prepared.

Likewise, the following products are prepared from the respective starting compounds:

7-( l-t-butoxy-n-propyl )-xanthone-2-carboxylic acid,

S-( l-t-butoxy-n-propyl)-xanthone-2-carboxylic acid,

7-( l-t-butoxy-isobutyl )xanthone-2carboxylic acid,

-( l-t-butoxy-isobutyl)-xanthone-2-carboxylic acid.

7-((cyclopropyl)-t-butoxymethyl)-xanthone-2-carboxylic acid 5( (cyclopropyl )-t-butoxymcthyl )-xanthone2-carboxylic acid,

7-((phcnyl-t-butoxymethyl)-xanthone-2-carboxylic acid,

5-((phenyl)tbutoxymethyl)-xanthone 2-carboxylic acid.

7-( l-t-butoxy-l-methylethyl)xanthone-2-carboxylic acid,

5-( l-tbutoxy 1 -methylethyl )-xanthone-2-carboxylic acid, and so forth.

EXAMPLE 2l Ten milliliters of dihydropyran are added to a solution of l g. of methyl 7-( l-hydroxyethyl)-xanthone-2- carboxylate in 50 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is crystallized from chloroform/methanol]- pyridine to yield methyl 7( 1-tetrahydropyran-2'-yl0xyethyl )-xanthone-Z-carboxylate.

Methyl 7-( Ltetrahydi'Opyran-Z '-yloxy l -methylethyl)-xanthone-2-carboxylate is prepared from methyl 7 l-hyd roxyl -methylethyl )-xanthone-2-carboxylate by conducting the above reaction at reflux for 2 hours.

Hydrolysis provides 7-( l-tetrahydropyran-2-yloxyethy])manthone-Z-carboxylic acid and 7-( l-tctrahydropyran-2'-yl0xy-1-methylcthyl)-xanthone2-carboxylic acid, respectively.

In like manner, 5-(1tetrahydropyran2'-yloxyethy])- xanthone-Z-carboxylic acid is prepared. By use of dihydrofuran in the above procedure, 7-(l-tetrahydrofuran-2'-yloxyethyl)-xanthone-2-carboxylic acid, 7-( tetrahydrofuran-Z'-yloxyl -methylethyl)-xanthone-2- carboxylic acid, 5-(l-tetrahydrofuran-2'-yloxyethyl)- xanthone-Z-carboxylic acid, 5-(l-tetrahydrofuran-2'- yloxy-l-methylethyl)-xanthone-2-carboxylic acid are prepared.

In like manner, the following compounds are prepared:

7-( l-tetrahydropyran-2 '-yloxy-n-propyl )-xanthone- 2-carboxylic acid,

7-( l-tetrahydropyran-2'-yloxy-is obutyl)-xanthone- 2-carboxylic acid,

7( l-tetrahydropyran-Z '-yloxy- 1 -ethylethyl)-xanthone-Z-carboxylic acid, and the tetrahydrofuran-2'- yloxy and C-5 substituted compounds corresponding thereto.

3.5 grams of methyl 7-( l-hydroxyethyl)-xanthone-2- carboxylate in 150 ml. of benzene and 500 mg. of p-toluene-sulfonic acid (dried by azeotropic distillation from benzene) are mixed together and the reaction mixture is treated with 4-methoxy-5,6-dihydro-2H- pyran, 1 ml. at a time until reaction is complete (followed by tlc). The reaction is quenched by addition of 9% ml. of triethylamine, washed with water, and crystallized with care from methanol containing pyridine to give methyl 7-( l-4-meth0xytetrahydropyran-4'-yloxefrom methyl 7( l-hydroxy-l-methylethyl)-xanthone-2- 36 carboxylate by conducting the above reaction at reflux for 2 hours.

Hydrolysis provides 7(l-4'-methoxytetrahydropyran-4-yloxyethyl)-xanthone-2-carboxylic acid and 7- l-4'-methoxy-tetrahydropyran-4-yloxyl -methylethyl)-xanthone-2-carboxylic acid respectively.

A solution of 1.4 g. of aluminum chloride in 25 ml. of tctrahydrofuran is treated with a solution of 0.4 g. of lithium aluminum hydride in lOO ml. of ether. Methyl 7-( l-4' methoxy-tetrahydropyran-4'-yloxyethyl)-xanthone-2-carboxylate (500 mg.) is extracted into the solution. After reduction is complete (monitored by tlc), saturated sodium chloride is added until a precipitate forms. This is filtered and the crude product is oxidized in acetic acid using excess sodium dichromate to give 7-( l-tetrahydropyran-4-yloxyethyl) xanthone-2carboxylic acid.

In like manner, the following compounds are prepared:

S-( l-4'-methoxytetrahydropyran-4'-yloxyethyl )-xanthone-2carboxylic acid,

5-( l-tetrahydropyran-4'-yloxyethyl )-xanthone-2- carboxylic acid,

7-( l-4'-ethoxytetrahydropyran-4'-yloxyethyl )-xan thone-2-carboxylic acid,

5-( l-4'-ethoxytetrahydropyran-4'-yloxyethyl )-xanthone2-carboxylic acid,

7-( l-4'-methoxytetrahydropyran4'-yloxyisobutyl)- xanthone-Z-carboxylic acid,

5-( l-4-methoxytetrahydropyran-4'-yloxyisobutyl xanthone-Lcarboxylic acid,

7-( l -tetrahydropyran-4'-yloxy-1 -methylethyl)-xanthone-Z-carboxylic acid,

5-( l'tetrahydropyran-4'-yloxyl -methylethyl )-xanthone-Z-carboxylic acid,

7-( l-4'-propoxytetrahydropyran4'-yloxy-n-propyl xanthone-Z-carboxylic acid, and

5-( l-4-propoxytetrahydropyran-4'-yloxy n-propyl xanthone-Z-carboxylic acid.

EXAMPLE 22 A mixture of 4.5 g. of 7-acetylxanthone-2-carboxylic acid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in ml. of dimethylformamide is stirred at room temperature for a period of 13 hours. After this period of time, the reaction mixture is poured into dilute hydrocloric acid-ice and the resultant precipitate is filtered off and washed to give methyl 7-acetylxanthone-2-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyl iodides so as to prepare the corresponding lower alkyl acid esters hereof, e.g. ethyl 7- acetylxanthone-2-carboxylate, n-propyl 7-acetylxanthone-2-caroxylate, isopropyl 7-acetylxanthone-2-carboxylate, n-propyl 7-acetylxanthone-2-carboxylate, isobutyl 7-acetylxanthone-2-carboxylate, sec-butyl 7- acetylxanthone-Z-carboxylate, t-butyl 7-acetylxanthone-Z-carboxylate, n-pentyl 7-acetylxanthone-2-carboxylate, and so forth.

In like manner, the other xanthone-Z-carboxylic acids thereof containing substituents at the C-5 or C-7 positions, prepared as described above, can be converted to the corresponding acid esters.

EXAMPLE 23 To a solution of 10 g. of 7-acetylxanthone-2-carboxylic acid in 200 ml. of ethanol is added the theoretical amount of sodium hydroxide dissolved in 200 ml. of

37 90% ethanol. The reaction mixture is then concentrated in vacuum to give sodium 7-acetylxanthone-2- carboxylate.

Sodium 7-(l-hydroxyethyl)-xanthone-2-carboxylic acid and sodium S-acetylxanthone-2-carboxylic acid are also thus prepared.

In a similar manner, the potassium and lithium salts are prepared. Similarly, by replacing the sodium salt by means of an appropriate metal salt reagent, e.g., calcium chloride, manganese chloride, and so forth, the other xanthone-Z-carboxylic acid salts are prepared, e.g., magnesium 7-acetylxanthone-2-carboxylate, calcium 7-acetylxanthone-2-carboxylate, aluminum 7- acetylxanthone-Z-carboxylate, ferrous 7-acetylxanthone-2-carboxylate, zinc 7-acetylxanthone-Z-carboxylate, manganese 7-acetylxanthone-2-carboxylate, ferric 7-acetylxanthone-Z-carboxylate, and so forth.

In a similar manner, the xanthone-2-carboxylic acid salts of the other C-S or C-7 substituted xanthone-2- carboxylic acids hereof are prepared.

EXAMPLE 24 To a mixture of 50 ml. of concentrated aqueous ammonia in 500 ml. of methanol there are added 20 g. of -acetylxanthone-Z-carboxylic acid. The resultant mix ture is stirred for 2 hours and is then evaporated to dryness to give the ammonium salt of 5-acetylxanthone-2- carboxylic acid.

A solution of g. of xanthone-2-carboxylic acid in 50 ml. of thionyl chloride is heated at reflux for 1 hour. Thereafter, the solution is evaporated to dryness to give the corresponding acid chloride to which is added a concentrated ethereal ammonia solution. The resultant solution is evaporated giving the ammonium salt of xanthone-2-carboxylic acid.

In like manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine in lieu of ammonia in the above procedures. Thus prepared, e.g.,

are

7-propionylxanthoneQ-carboxylic acid amide,

N-methyl 7-isobutyrylxanthone-2-carboxylic amide,

N,N-dimethyl 5-( l-hydroxyethyl)-xanthone-2-carboxylic acid amide,

N,N-diethyl 7-( l-hydroxyl-methyU-xanthone-2- carboxylic acid amide.

N-ethyl 7-benzoylxanthone-2-carboxylic acid amide,

N-n-propyl 7-furylxanthone-2-carboxylic acid amide, and so forth.

acid

EXAMPLE 25 To a mixture of g. of procaine and 500 ml. of aqueous methanol are added 20 g. of 7-isobutyrylxanthone-2-carboxylic acid. The resultant mixture is stirred at room temperature for 16 hours. it is then evaporated under reduced pressure to give the procaine salt of 7-isobutyrylxanthone-2-carboxylic acid.

Similarly, the lysine, caffeine. and argine salts thereof are obtained. in like manner, the e.g., procaine, lysine, caffeine, and arginine salts of the other 5- and 7substituted xanthone-2carboxylic acids are obtained, e.g.,

the procaine salt of 7-acetylxanthone-Z-carboxylic acid, the caffeine salt of 5-( l-hydroxy-n-propyHxanthone-Z-carboxylic acid, the lysine salt of 7-hydroxymethylxanthone-Z-carboxylic acid, the procaine salt of 5-hydroxymethylxanthone-2-carboxylic acid, and the arginine salt of 5-acetylxanthone-2carboxylic acid.

EXAMPLE 26 The following procedures illustrate the method by which the pharmaceutical compositions of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in ml. of a (9.47 g./l water) sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00 g./l. water) solution (20 ml.) is then added thereto. The resultant solution having a pH of 7.38 is sterilized in an autoclave. This vehicle is then added to solid, dry xanthone-2-carboxylic acid to give a preparation suitable for intravenous injection containing 2.5 mg. of xanthone-Z-carboxylic acid per ml. of total composition.

EXAMPLE 27 The following procedure illustrates a test procedure for the compounds hereof.

Normal female (Sprague-Dawley) rats of to 200 grams each are passively sensitized intradermally by injection of rat anti-egg albumin reaginic sera. After 24 hours, each rat is challenged intravenously with 1.75 ml. of 0.4% Evans blue, 1 mg. egg albumin plus l().0 mg. of xanthone-2-carboxylic acid. Control rats receive no xanthone-Z-carboxylic acid. The dermal bluing is recorded 15 to 25 minutes later. The rats which receive the xanthone-2-carboxylic acid exhibit a I00 percent inhibition of allergic reaction whereas the control rats exhibit no inhibition.

The above procedure is repeated using 7-acetylxanthone-2-carboxylic acid, with similar results. The above procedure is repeated using oral administration, with similar results.

Xanthone-Z-carboxylic acid compounds are administered by gavage at a dose of 20 mg. per animal 15 minutes prior to challenge. Twenty to 30 minutes after challenge the degree of dermal bluing is read, with similar results.

inhibition of reaginic antigenantibody reactions in rats is regarded as representative of inhibition of human reaginic antigen-antibody reactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent of provoked degree of asthma condition by changes in airway resistance on expiration. The subject compounds are administered as an aerosol by inhalation before antigen challenge. Prevention of asthmatic conditions upon the administration of the compounds is evidence by a decrease in airway resistance and other subjective improvements, e.g., reduced cough.

What is claimed is:

l. A compound selected from those represented by the following formulas: 

1. A COMPOUND SELECTED FROM THOSE REPRESENTED BY THE FORLLOWING FORMULAS:
 2. The compound acCording to claim 1 of formula (A).
 3. The compound according to claim 2 wherein R is the group
 4. The compound according to claim 3 wherein R1 is hydrogen.
 5. The compound according to claim 4 wherein R2 is lower alkyl.
 6. The compound according to claim 5 wherein R'' is hydrogen and R2 is methyl; 5-(1-hydroxyethyl)-xanthone-2-carboxylic acid.
 7. The compound according to claim 3 wherein each of R1 and R2 is lower alkyl.
 8. The compound according to claim 7 wherein R'' is hydrogen and each of R1 and R2 is methyl; 5-(1-hydroxy-1-methylethyl)-xanthone-2-carboxylic acid.
 9. The compound according to claim 1 of formula (B).
 10. The compound according to claim 9 wherein R is the group
 11. The compound according to claim 10 wherein R1 is hydrogen.
 12. The compound according to claim 10 wherein R2 is lower alkyl.
 13. The compound according to claim 12 wherein R'' is hydrogen and R2 is methyl; 7-(1-hydroxyethyl)-xanthone-2-carboxylic acid.
 14. The compound according to claim 10 wherein each of R1 and R2 is lower alkyl.
 15. The compound according to claim 14 wherein R'' is hydrogen and each of R1 and R2 is methyl; 7-(1-hydroxy-1-methylethyl)-xanthone-2-carboxylic acid.
 16. The sodium salts of the compounds according to claim
 1. 17. The salts according to claim 16 of formula (B).
 18. The compound according to claim 17 which is sodium 7-(1-hydroxyethyl)-xanthone-2-carboxylate. 